Radioimmunotherapy (RIT) has been the subject of investigations since the early 1970s. A tumor antigen-binding protein is labeled with a therapeutic radionuclide and administered systemically—the radionuclide decay results in lethal radiation that putatively destroys cancer cells. RIT of lymphoma has shown great promise (1-5), and two anti-CD20 agents are approved by the Food and Drug Administration (FDA) for clinical use. There are no pivotal or phase 3 trials in solid tumor RIT, partly because the need for nonimmunogenic proteins necessitated the development of chimeric and humanized antibodies, and also because tumor radiation-absorbed dose with radiolabeled intact immunoglobulin has been inadequate in most of the systems studied.

Solid tumor RIT has been studied in various cancers: breast, ovarian, color-ectal, renal, prostate, and brain. The only positive outcome in most of these studies has been disease stabilization in many patients. No outcome indicators have yet been sufficiently promising to warrant phase 2 or other development with nonmye-loablative RIT. These initial clinical trials have been very instructive in the development of "optimal" strategies, including antigen-binding construct design, optimal radionuclides for tumors of various sizes, and treatment delivery systems.

Immunogenicity of the antigen-binding construct is not the only constraint facing RIT for solid tumors. Antigenic modulation and heterogeneity, barriers to

^The author wishes to thank E. Alexander Wills for helpful critique and proof-reading.

penetration of protein into tumor, and adequate relative tumor uptake and residence time are some of the other factors (6,7) that are still problematic for successful therapy. Bone marrow toxicity without treatment response has been a serious constraint as well.

Understanding RIT requires the understanding of therapeutic radionuclides and antigen-binding constructs. The unique biology of solid tumors necessitates the development of strategies for rational treatment designs that address the biological complexity of solid tumors.

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